Summary Challenge Area, 05 Comparative Effectiveness Research (CER): Challenge Topic NHLBI-05-HL-104* Reducing Cardiovascular Risk in Moderate-Risk and Asymptomatic Patients." Our project is entitled "Novel Technologies to Identify Preclinical Coronary Disease in High Risk Families." Its prime purpose is to compare an innovative coronary artery imaging technology with a standard imaging method in the detection of very early coronary disease in people who are at high risk but who have not had symptoms or a clinical coronary disease event. Coronary atherogenesis begins well before manifest clinical coronary disease (CAD). If occult CAD and its extent could be accurately identified during the preclinical phase, targeted intensive preventive therapies could be tested that may mitigate CAD events. In this study we will apply a comparative effectiveness research paradigm to a susceptible population of asymptomatic first degree adult relatives of persons with known premature CAD, all easily identifiable by family history, with a CAD risk that is 2-5 times that of the general population. We have extensive genotyping in ~3000 individuals in a prospective family study, GeneSTAR (Genetic Determinants of Atherosclerosis Risk). The goal of this proposed challenge grant study is to advance personalized preventive medicine using a comparative effectiveness research model. We will compare the relative effectiveness of CT CAC and MDCTA for identifying subjects with latent preclinical CAD who would represent appropriate targets for intensive preventive therapies. Our primary specific aims are to (1) evaluate both (the extent of calcified and noncalcified coronary plaque using MDCTA, and coronary calcium score (CAC) in 1000 22 to 75 year old apparently healthy siblings and adult offspring of probands with known premature CAD (<60 years of age) from the GeneSTAR study. (2) determine the relationship of traditional risk factors (Framingham Global Risk Score), and hsCRP to outcomes to determine the optimal identification of persons with significant preclinical CAD, and (3) determine whether the addition of known genetic risk variants for CAD improve selection of subjects for CT or MDCTA. Data will be used to general reference values for plaque volumes and to determine the value of MDCTA as a method to track responsiveness to therapy in a subsequent primary prevention trial. The goal is also to create jobs and advance science more quickly. We plan to do this by creating 2 new jobs, supporting 2-4 others, and by providing funds to retain people in their current positions. Our work is also predicated on the tenet that the project should yield data that will provide for subsequent follow-up and for a larger primary prevention clinical trial. Every year The Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create or retain at least 7-10 jobs, including 2 direct new full-time employees. Public Health Relevance: The goal of this proposed challenge grant study is to advance personalized preventive medicine using a comparative effectiveness research model to compare the relative effectiveness two methods for looking at coronary artery plaque. The purpose is to identify subjects with latent preclinical CAD who would represent appropriate targets for intensive preventive therapies.